Cell Penetrating Peptides: Classification, Mechanisms, Methods of Study, and Applications

Abstract

Cell‐penetrating peptides (CPPs) encompass a class of peptides that possess the remarkable ability to cross cell membranes and deliver various types of cargoes, including drugs, nucleic acids, and proteins, into cells. For this reason, CPPs are largely investigated in drug delivery applications in the context of many diseases, such as cancer, diabetes, and genetic disorders. While sharing this functionality and some common structural features, such as a high content of positively charged amino acids, CPPs represent an extremely diverse group of elements, which can differentiate under many aspects. In this review, we summarize the most common characteristics of CPPs, introduce their main distinctive features, mechanistic aspects that drive their function, and outline the most widely used techniques for their structural and functional studies. We highlight current gaps and future perspectives in this field, which have the potential to significantly impact the future field of drug delivery and therapeutics.

Engineering the interaction of short antimicrobial peptides with bacterial barriers

“…57 Typically, the cell penetration efficiency of peptides tends to increase with their amphipathicity content, but when a high value of hydrophobicity is reached, peptides predominantly remain on plasma cell membranes. 58 Overall it is not possible, from the reported literature, to correlate a specific secondary structure with an efficient passage through the membrane, as the uptake process was obtained with peptides characterized by an α-helical, a β-sheet, or a random coil structure (Table 1).…”

Potential of Cell-Penetrating Peptide-Conjugated Antisense Oligonucleotides for the Treatment of SMA

“…Macropinocytosis is the most reported endocytic pathway for CPP uptake and involves the plasma membrane deforming and protruding to encapsulate the CPP and its cargo in an endocytic vesicle that subsequently buds off the membrane and can release its contents within the cell [109]. Although micropinocytosis occurs independent of receptors, the protrusion of the cell membrane is regulated by a group of kinases and ATPases [86]. Receptor-mediated endocytosis involves the inward folding of the cellular membrane upon of the CPP with a cell membrane receptor.…”

A Structure Independent Molecular Fragment Interfuse Model for Mesoscale Dissipative Particle Dynamics Simulation of Peptides

“…Peptides have a wide range of applications in medicine, drug delivery, and tissue engineering. − These include, among others, peptides as antimicrobial, anticancer, and cell penetrating agents, as vaccines and biosensors, as self-assembly agents to form hierarchical multiscale structures, and as interference peptides in precision medicine. − Recently, peptides based on the recognition sites of morphogenetic proteins have received attention as an alternative to protein therapy in tissue engineering to guide differentiation and maturation of transplanted cells to the desired lineage to reduce side effects like immunogenic response and tumorigenicity. − However, peptides derived from morphogenetic and other proteins have orders of magnitude lower biological activity. , This lower activity is attributed to misfolding in the absence of other protein sequences (conformational differences between the peptide as a part of the protein versus a free molecule), which further causes peptide aggregation and micelle formation . Furthermore, natural peptides are susceptible to degradation by proteolytic enzymes and their function is limited by short half-life in physiological medium .…”